Nitric oxide, an important regulator of perfusion-contraction matching in conscious pigs

We examined whether nitric oxide (NO) inhibition during moderate reduction in coronary blood flow (CBF) would affect perfusion-contraction matching. Coronary stenosis (CS) was induced in conscious pigs, which resulted in a stable 39 +/- 1% reduction in CBF for 1.5 h. Ischemic zone wall thickening (IZWT) decreased by an average of 56 +/- 2% during CS from 2.7 +/- 0.2 mm. After reperfusion, myocardial stunning was observed, but this recovered without evidence of necrosis. After recovery and subsequent administration of systemic NO synthase inhibition (N(omega)-nitro-L-arginine, 25 mg. kg(-1). day(-1) x 3 days), CS for 1.5 h reduced CBF similarly but decreased IZWT significantly more, P < 0.05, by 89 +/- 5%. Myocardial stunning, i.e., the decrease in IZWT at 12 h post-CS, was more severe (-65 +/- 5% vs. -21 +/- 3%), P < 0.05. Furthermore, CS during NO synthase inhibition resulted in multifocal subendocardial areas of necrosis in the area at risk. These data suggest that in the intact, conscious pig, NO inhibition prevents perfusion-contraction matching, resulting in intensification of post-ischemic stunning and development of subendocardial necrosis.     

Metabolic protection of the reperfused canine endocardium by the thromboxane synthetase inhibitor, dazoxiben

This study investigated whether dazoxiben, a thromboxane synthesis inhibitor, could reverse regional contractile dysfunction and protect against adenine nucleotide loss in the "stunned myocardium". Hearts from anesthetized dogs were "stunned" by 15 min of left anterior descending coronary artery occlusion followed by 3 hr of reperfusion. Left ventricular segment shortening (%SS) and regional myocardial blood flow (RMBF) were measured by sonomicrometry and the radioactive microsphere technique, respectively. Local coronary venous blood was withdrawn and thromboxane A2 and prostacyclin measured by radioimmunoassay. Transmural biopsies from the reperfused and nonischemic areas were taken at 3 hr following reperfusion for tissue metabolite analysis. During ischemia, %SS, RMBF and area at risk were decreased to similar levels in both control and dazoxiben-treated hearts indicating equivalent degrees of flow deprivation. During reperfusion, %SS recovered only partially and was not significantly improved by dazoxiben. Dazoxiben augmented peak prostacyclin production (123 +/- 31% vs. 292 +/- 49% of preocclusion values) following reperfusion, while it completely blocked thromboxane A2 production. Dazoxiben attenuated the decline in endocardial ATP (69 +/- 5% vs. 92 +/- 9% normalized to the nonischemic zone) and total adenine nucleotides. The results indicate that dazoxiben may elicit a cardioprotective effect on energy metabolism in the reperfused heart, but this is dissociated from any improvement in regional contractile function.     

Progressive loss of perfusion-contraction matching during sustained moderate ischemia in pigs

It is unclear whether perfusion-contraction matching (PCM) is maintained during prolonged myocardial ischemia. In 27 anesthetized pigs, left anterior descending coronary arterial inflow was reduced to decrease an anterior work index (WI) at 5 min of hypoperfusion by 40% and then maintained at this level for 12 or 24 h. With 12 h of hypoperfusion, the myocardium remained viable in 6 of 7 pigs (with triphenyltetrazolium chloride; TTC) and with 24 h of hypoperfusion in 5 of 11 pigs (TTC, histology). The reduction in WI to 62 +/- 4 and 62 +/- 3% of baseline in the two groups was matched to the reduction of transmural blood flow (TBF; microspheres) at 5 min of hypoperfusion, averaging 59 +/- 4 and 60 +/- 2% of baseline. With prolonged hypoperfusion, WI decreased to 30 +/- 5% at 12 h and 18 +/- 3% at 24 h; TBF remained unchanged (53 +/- 4 and 54 +/- 4%). The added calcium concentration required for the half-maximal increase in WI increased from 121 +/- 25 microg/ml blood at baseline to 192 +/- 26 microg/ml blood at 12 h of hypoperfusion. Thus, with hypoperfusion for 24 h, PCM is progressively lost, and calcium responsiveness is reduced.     

Impaired resting perfusion in viable myocardium distal to chronic coronary stenosis in rats

Chronic coronary artery stenosis results in patchy necrosis in the dependent myocardium and impairs global and regional left ventricular (LV) function in rats in vivo. The aim of the present study was to compare regional myocardial blood flow (RMBF) and function (F) in poststenotic myocardium by using magnetic resonance imaging (MRI) and to compare MRI blood flow changes to histological alterations to assess whether RMBF in the viable poststenotic tissue remains normal. MRI was performed in 11 anesthetized Wistar rats with 2-wk stenosis of the left coronary artery. Postmortem, the extent of fibrotic tissue was quantified. Poststenotic RMBF was significantly reduced to 2.21 +/- 0.30 ml.g(-1).min(-1) compared with RMBF in the remote myocardium (4.05 +/- 0.50 ml.g(-1).min(-1)). A significant relationship between the poststenotic RMBF (%remote area) and the poststenotic F (%remote myocardium) was calculated (r = 0.61, P < 0.05). Assuming perfusion in scar tissue to be 32 +/- 5% of perfusion of remote myocardium, as measured in five additional rats, and that in remote myocardium to be 114 +/- 25% of that in normal myocardium, as assessed in five sham rats, the calculated perfusion in partially fibrotic tissue samples (35.7 +/- 5.2% of analyzed area) was 2.88 +/- 0.18 ml.g(-1).min(-1), whereas measured MRI perfusion was only 1.86 +/- 0.24 ml.g(-1).min(-1) (P < 0.05). These results indicate that resting perfusion in viable poststenotic myocardium is moderately reduced. Alterations in global and regional LV function are therefore secondary to both patchy fibrosis and reduced resting perfusion.     

Simulated microgravity enhances cerebral artery vasoconstriction and vascular resistance through endothelial nitric oxide mechanism

Growing evidence suggests that cardiac enkephalins and their receptors are involved in ischemic preconditioning (IPC). Because there is no evidence for vesicular storage of small bioactive enkephalins in the heart, studies were designed to test the hypothesis that ischemia depletes cardiac enkephalins and that IPC preserves the same enkephalins by accelerating their processing from the larger proenkephalin precursor (PEP) pool. The precursors and two bioactive representatives, Met-enkephalin (ME) and Met-enkephalin-Arg-Phe (MEAP), were separated by size-exclusion chromatography and quantified by radioimmunoassay. Isolated perfused rat hearts were prepared and exposed to global ischemia. After 30 min of global ischemia and 40 min of reflow, the PEP pool was reduced (from 17.99 +/- 1.52 to 14.20 +/- 2.38 pmol/g wet wt), MEAP increased by 53%, and ME declined by 68%. The sum of the two smaller peptides was unchanged (9.78 +/- 0.83 vs. 9.33 +/- 2.81). Thus the total enkephalin peptide content was not altered (27.77 +/- 1.69 vs. 24.10 +/- 4.75). Peptide distribution after ischemia and reflow was also unaltered by pretreatment with peptidase inhibitors. However, when the hearts were preconditioned, the PEP pool remained significantly lower and both of the bioactive peptides, MEAP and ME, were elevated (+49% and +86%, respectively). The decline in the PEP pool was prevented by peptidase inhibition and the rise in MEAP was exaggerated. In separate protocols, synthetic enkephalins (ME, MEAP, and Leu-enkephalin) were added to the coronary inflow before 30 min of global ischemia and throughout the subsequent reflow. The added enkephalins (10(-8) M) had no inotropic effect on baseline function but completely prevented the mechanical dysfunction observed in untreated controls during reflow. Thus IPC appears to increase available bioactive enkephalins (MEAP + ME) within the heart by enhancing synthesis of precursors and their subsequent processing from the PEP pool.     

Coronary sinus occlusion enhances coronary collateral flow and reduces subendocardial ischemia

On the hypothesis that coronary sinus occlusion (CSO) may reduce myocardial ischemia, we examined the effects of CSO on coronary collateral blood flow and on the distribution of regional myocardial blood flow (RMBF) in dogs. Thirty-eight anesthetized dogs underwent occlusion of the left anterior descending coronary artery with or without CSO and intact vasomotor tone. We measured RMBF and intramyocardial pressure (IMP) in the subendocardium (Endo) and subepicardium (Epi) separately. With intact vasomotor tone, CSO during ischemia significantly increased RMBF in the ischemic region (IR), particularly in Endo from 0.17 +/- 0.03 to 0.33 +/- 0.05 ml x min(-1) x g(-1) (P < 0.05), and increased the Endo/Epi from 0.59 +/- 0.10 to 1.15 +/- 0.15 (P < 0.01). These effects of CSO were partially abolished by adenosine. However, the Endo/Epi was still increased from 0.90 +/- 0.13 to 2.09 +/- 0.30 (P < 0.01). The changes in RMBF in IR were significantly correlated with the peak CS pressure during CSO. The Endo/Epi of IMP in IR was significantly decreased during CSO. In conclusion, CSO potentially enhances coronary collateral flow, and preserves the ischemic myocardium, especially in Endo.     

Human respiratory muscle blood flow measured by near-infrared spectroscopy and indocyanine green.

Measurement of respiratory muscle blood flow (RMBF) in humans has important implications for understanding patterns of blood flow distribution during exercise in healthy individuals and those with chronic disease. Previous studies examining RMBF in humans have required invasive methods on anesthetized subjects. To assess RMBF in awake subjects, we applied an indicator-dilution method using near-infrared spectroscopy (NIRS) and the light-absorbing tracer indocyanine green dye (ICG). NIRS optodes were placed on the left seventh intercostal space at the apposition of the costal diaphragm and on an inactive control muscle (vastus lateralis). The primary respiratory muscles within view of the NIRS optodes include the internal and external intercostals. Intravenous bolus injection of ICG allowed for cardiac output (by the conventional dye-dilution method with arterial sampling), RMBF, and vastus lateralis blood flow to be quantified simultaneously. Esophageal and gastric pressures were also measured to calculate the work of breathing and transdiaphragmatic pressure. Measurements were obtained in five conscious humans during both resting breathing and three separate 5-min bouts of constant isocapnic hyperpnea at 27.1 +/- 3.2, 56.0 +/- 6.1, and 75.9 +/- 5.7% of maximum minute ventilation as determined on a previous maximal exercise test. RMBF progressively increased (9.9 +/- 0.6, 14.8 +/- 2.7, 29.9 +/- 5.8, and 50.1 +/- 12.5 ml 100 ml(-1) min(-1), respectively) with increasing levels of ventilation while blood flow to the inactive control muscle remained constant (10.4 +/- 1.4, 8.7 +/- 0.7, 12.9 +/- 1.7, and 12.2 +/- 1.8 ml 100 ml(-1) min(-1), respectively). As ventilation rose, RMBF was closely and significantly correlated with 1) cardiac output (r = 0.994, P = 0.006), 2) the work of breathing (r = 0.995, P = 0.005), and 3) transdiaphragmatic pressure (r = 0.998, P = 0.002). These data suggest that the NIRS-ICG technique provides a feasible and sensitive index of RMBF at different levels of ventilation in humans.     

Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit

The aim was to define the degree and time course of reperfusion-related expansion of no reflow. In five groups of anesthetized, open-chest rabbits (30-min coronary occlusion and different durations of reperfusion), anatomic no reflow was determined by injection of thioflavin S at the end of reperfusion and compared with regional myocardial blood flow (RMBF; radioactive microspheres) and infarct size (triphenyltetrazolium). The area of no reflow progressively increased from 12.2 +/- 4.2% of the risk area after 2 min of reperfusion to 30.8 +/- 3.1% after 2 h and 34.9 +/- 3.3% after 8 h and significantly correlated with infarct size after 1 h of reperfusion (r = 0.88-0.97). This rapid expansion of no reflow predominantly occurred during the first 2 h, finally encompassing approximately 80% of the infarct size, and was accompanied by a decrease of RMBF within the risk area, being hyperemic after 2 min of reperfusion (3.78 +/- 0.75 ml x min(-1) x g(-1)) and plateauing at a level of approximately 0.9 ml x min(-1) x g(-1) by 2 and 8 h of reperfusion (preischemic RMBF: 2.06 +/- 0.01 ml x min(-1) x g(-1)). The development of macroscopic hemorrhage lagged behind no reflow, was closely correlated with it, and may be the consequence of microvascular damage.     

Respiratory muscle blood flow in oleic acid-induced pulmonary edema

If respiratory muscle blood flow (RMBF) demands in pulmonary edema are large enough, an imbalance between supply and demand could lead to respiratory muscle failure. Therefore, to determine the magnitude of RMBF in this condition we produced pulmonary edema by injecting oleic acid into the pulmonary circulation and measured RMBF with radiolabeled microspheres injected into the left atrium. We then related changes in muscle blood flow to changes in respiratory variables including frequency of breathing (fb, breaths/min), tidal volume (VT, ml), ventilation (VE, ml . kg-1 . min-1), pleural pressure-time index (PTI, cmH2O), and dynamic compliance (Cdyn, 1/cmH2O) at 0 (control), 30, 60, and 120 min. Cardiac output and blood pressure did not change throughout the experiment, but hypoxia became progressively more severe with a final PO2 of 37 +/- 10 Torr. With pulmonary edema, fb rose from a control value of 32 +/- 13 to 111 +/- 33 at peak, VE rose from 237 +/- 90 to 806 +/- 188, but VT did not change. PTI rose from 54 +/- 16 to 180 +/- 48, and Cdyn decreased from 0.06 +/- 0.02 to 2.02 +/- 0.01. Diaphragmatic blood flow (Qdi) rose from 16.0 +/- 6.26 to 120.1 +/- 54.5 ml . min-1 X 100 g-1 and accounted for 55% of the total RMBF of 217 +/- 100 ml/min. The RMBF accounted for 11.4 +/- 4.7% of the cardiac output at peak affect. The rise in Qdi was best predicted by PTI and to a smaller extent by PO2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term infusion of Met5-enkephalin fails to protect murine hearts against ischemia-reperfusion injury

Recently, we reported that exogenous administration of Met(5)-enkephalin (ME) for 24 h reduces infarct size after ischemia-reperfusion in rabbits. In the present study, we tested whether ME-induced cardioprotection is exhibited in murine hearts and whether chronic infusion of this peptide can render hearts tolerant to ischemia. Barbiturate-anesthetized open-chest mice (C57BL/6J) were subjected to regional myocardial ischemia-reperfusion (45 min of occlusion and 20 min of reperfusion). Mice received saline vehicle or ME for 24 h or 2 wk before undergoing regional myocardial ischemia-reperfusion or for 24 h followed by a 24-h delay before regional myocardial ischemia-reperfusion. Infarct size was measured with propidium iodide and is expressed as a percentage of the area at risk. Infarcts were smaller after infusion of ME for 24 h than with vehicle control: 49.2 +/- 9.0% vs. 22.2 +/- 3.2% (P < 0.01). In contrast, administration of ME for 2 wk failed to elicit cardioprotection: 36.5 +/- 9.1% and 41.4 +/- 8.2% for control and ME, respectively (P = not significant). When a 24-h delay was imposed between the end of drug treatment and the onset of the ischemic insult, cardioprotection was lost: 38.5 +/- 6.1% and 42.8 +/- 6.6% for control and ME, respectively (P = not significant). Chronic sustained exogenous infusion of the endogenously produced opioid peptide ME is associated with loss of the cardioprotection that is observed with 24 h of infusion. Furthermore, in this in vivo murine model, ME failed to induce delayed tolerance to myocardial ischemia-reperfusion.     

GABA对大鼠下丘脑正中隆起LHRH释放调节的研究

本研究应用大鼠下丘脑正中隆起(ME),观察 γ-氨基丁酸(GABA)和去甲肾上腺素(NA)对下丘脑促黄体生成激素释放激素(LHRH)神经元末梢分泌作用的影响。结果发现:GABA(10~(-6)mol/L)可显著促进 ME 的 LHRH 和 NA 的释放,即 LHRH 释放量由27.3±2.5pg/100ul 增加至150.4±27.9pg/100μl;NA 释放量由50.9±4.2pg/100μl 增加至105.5±19.1pg/100ul,两者与对照组相比有显著差异(P<0.01)。GABA 这些作用可被受体拮抗剂荷包牡丹碱(Bicuculline)所翻转。当荷包牡丹碱和 GABA(10~(-6)mol/L)同时存在于 ME 的培灌液中,LHRH 的分泌量下降为18.2±1.9pg/100μl,而 NA 分泌量下降为43.9±3.4pg/100μl。在内源性 NA 被利血平耗竭时,LHRH 的释放量仅增加26.5%,而 GABA 能使正常大鼠 LHRH 释放量增加451.9%。本研究提示:GABA 可促进下丘脑 ME 释放 LHRH,这一作用可能通过 NA 中介。     

Is microvascular protection by cariporide and ischemic preconditioning causally linked to myocardial salvage?

Two independent cardioprotective interventions, Na(+)/H(+) exchange inhibition and ischemic preconditioning (PC), were investigated with respect to differential effects on microvascular and myocardial salvage in anesthetized rabbits (30 min of ischemia, 180 min of reperfusion). Cariporide (Car, 300 microg/kg) administered before occlusion and PC reduced infarct size (IS) as measured by triphenyltetrazolium staining [control, 46.0 +/- 4.2% of risk area (RA); Car, 17.6 +/- 3.7% (P < 0.01); PC, 27.5 +/- 4.1% (P < 0.01)] and concomitantly decreased the area of anatomic no reflow (ANR) as measured by thioflavin S staining [control, 40.4 +/- 3.7%; Car, 19.0 +/- 2.9% (P < 0.01); PC, 26.9 +/- 3.4% (P < 0.05)]. Regional myocardial blood flow (RMBF, measured by radioactive microspheres) in the RA, which deteriorated between 30 and 180 min of reperfusion (control, from 79 +/- 6 to 26 +/- 2% of nonischemic flow), was shifted to higher values with both treatments [Car, from 110 +/- 12 to 49 +/- 7% (P < 0.05); PC, from 109 +/- 8 to 38 +/- 6% (P < 0.05)]. However, neither intervention uncoupled the close relationship between IS and ANR (r = 0.92-0.95) or RMBF. Car given at reperfusion did not alter IS, ANR, RMBF, or the close interrelationships. Because size and spatial distribution of no reflow and myocardial necrosis remained closely coupled with independent cardioprotective interventions, a potential causal connection between microvascular and myocardial salvage is discussed.     

Thermogenesis in response to various intakes of palatable food

Complete energy balance studies were made on groups of overfed (A) and underfed (B) Wistar rats. In experiment A one group was fed cafeteria diet ad libitum (the intake was 29% larger than the control), two other groups were fed the same diet but in restricted quantities (18 and 9% above control), and a fourth group, fed a stock diet, served as control. In experiment B, caloric intake was restricted by 12 and 31% in two groups fed cafeteria diet, and by 21 and 34% in two other groups fed stock diet. The experiments lasted 41 days and during that period the protein gain was comparable between the control and the cafeteria-29% group (643.4 +/- 33.3 vs. 578.1 +/- 25.0) but the fat gain was significantly different between the two groups (863.2 +/- 81.6 vs. 1663.2 +/- 99.8 kJ). When energy expenditure (EE) (metabolizable energy less storage added to the cost of storage) is expressed as a percentage of metabolizable energy (ME) intake no significant difference was found among the groups. The average value was congruent to 75%. This finding would not support the presence of dietary-induced thermogenesis in animals overfed on the cafeteria diet. However, since the obligatory cost associated with storing energy would not explain the higher EE of the overfed groups, it is suggested that the level of ME intake exerts continuous proportional regulatory action on EE and, as a result, energy is spared by underfeeding and it is wasted by overfeeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial susceptibility to ischemic-reperfusion injury in a prediabetic model of dietary-induced obesity

We assessed the myocardial susceptibility to ischemic-reperfusion injury in obese rat hearts in the absence and the presence of predicted circulating concentrations of insulin and fatty acids. Feeding rats a high-calorie diet resulted in increases in body weight, visceral fat content, cardiac hypertrophy, plasma insulin, nonesterified free fatty acid, and triglyceride concentrations. In the absence of both insulin and fatty acids in the coronary perfusate, the hearts of obese rats developed an increased infarct size (41.9 +/- 1.9% for obese vs. 22.9 +/- 2.3% for control, P < 0.05) and a reduced percent recovery of aortic output (4.2 +/- 4.2% for obese vs. 27.7 +/- 3.4% for controls, P < 0.05) after coronary artery occlusion and reperfusion. In the presence of insulin in the coronary perfusate, a cardioprotective effect was noted in both groups, an action that was greater in hearts from obese compared with control rats and which abolished the obesity-induced changes in infarct size (13.8 +/- 1.2% for controls vs. 21.0 +/- 1.6% for obese), and percent recovery of aortic output (60.2 +/- 4.7% for controls vs. 45.7 +/- 9.4% for obese). Fatty acids (0.7 mM, control; and 1.5 mM, obese) added to the coronary perfusate with in vivo concentrations of insulin dramatically increased infarct size (48.2 +/- 3.1% for obese, and 37.5 +/- 2.7% for control; P < 0.05 vs. without fatty acids) and decreased percent aortic output recovery (control, 10.4 +/- 5.2%, and obese 7.8 +/- 3.5%; P < 0.05 vs. without fatty acids) in both groups to similar values. In conclusion, in obesity, the impact of an increased susceptibility of the myocardium to ischemic-reperfusion injury on myocardial injury is likely to be overshadowed by the comparatively greater roles played by predicted increases in circulating insulin and fatty acids found in vivo. These data support the notion that adiposity per se is unlikely to be a valuable predictor of outcomes in ischemic-reperfusion injury.     

Sustained exogenous administration of Met5-enkephalin protects against infarction in vivo

The opioid antagonist naloxone abolishes infarct limitation by myocardial ischemic preconditioning, suggesting that one or more endogenous opioid peptides can mediate cardiac protection against ischemic damage. We tested the hypothesis that the naturally occurring opioid peptide Met5-enkephalin (ME) modulates myocardial infarct size in vivo. Experiments were conducted in barbiturate-anesthetized open-chest rabbits subjected to regional myocardial ischemia-reperfusion. ME was administered via osmotic minipump for 24 h. Infarct size was assessed with tetrazolium and is expressed as a percentage of the area at risk. Exogenous ME reduced the amount of the risk zone infarcted by approximately 60% compared with saline-treated controls. ME-induced protection was sensitive to opioid receptor blockade with naloxone [NAL 50 +/- 2% vs. ME + NAL 39 +/- 3%, P = not significant (NS)] and also to blockade of sarcolemmal and mitochondrial ATP-sensitive K+ (KATP) channels [5-hydroxydecanoate (5-HD) 33 +/- 3% vs. ME + 5-HD 43 +/- 8%, P = NS; and HMR-1098 60 +/- 3% vs. ME + HMR-1098 54 +/- 7%, P = NS]. We conclude that ME limits ischemic injury in vivo by an opioid receptor-mediated mechanism that involves both sarcolemmal and mitochondrial KATP channels.     

Preconditioning of salvaged myocardium in conscious rabbits with postinfarction dysfunction

Protection against postinfarction myocardial dysfunction is modest with classic preconditioning (PC). We investigated whether multiple cycles of PC could improve this protection and whether postinfarction dysfunction only depends on the amount of viable tissue. Eighteen rabbits were chronically instrumented with coronary occluders and ultrasonic crystals (segment shortening, SH) in the ischemic zone. A control group underwent 30-min coronary artery occlusion (CAO) with 72-h reperfusion (CAR). In two other groups, PC was induced by six 4-min CAO/4-min CAR cycles (PCx6) or one 5-min CAO/10-min CAR cycle (PCx1). After 72-h CAR, depression in SH was reduced in PCx1 (-68 +/- 7% from baseline) and to a greater extent in PCx6 (-18 +/- 10%) vs. control (-99 +/- 7%; all P < 0.05). Infarct sizes were reduced in PCx1 (15 +/- 2%) and to a greater extent in PCx6 (3 +/- 1%) vs. control (46 +/- 5%; P < 0.05). Contractility of salvaged myocardium was evaluated by calculating the ratio between SH at 72-h CAR and the amount of viable tissue. This index was enhanced in PCx1 (0.39 +/- 0.07, P < 0.05) and to a greater extent in PCx6 (0.82 +/- 0.09) vs. control (0.0 +/- 0.10). This differential effect of PC was not related to changes in apoptosis, endothelial nitric oxide synthase (NOS) expression, or macrophages infiltration but, rather, to blunted inducible NOS expression in PCx6 vs. control and PCx1. Thus multiple cycles of PC induced an almost complete protection against postinfarction dysfunction, potentially involving beneficial effects on salvaged myocardium.     

Changes in cardiorespiratory fitness and coronary heart disease risk factors following 24 wk of moderate- or high-intensity exercise of equal energy cost.

This study was designed to investigate the effect of exercise intensity on cardiorespiratory fitness and coronary heart disease risk factors. Maximum oxygen consumption (Vo(2 max)), lipid, lipoprotein, and fibrinogen concentrations were measured in 64 previously sedentary men before random allocation to a nonexercise control group, a moderate-intensity exercise group (three 400-kcal sessions per week at 60% of Vo(2 max)), or a high-intensity exercise group (three 400-kcal sessions per week at 80% of Vo(2 max)). Subjects were instructed to maintain their normal dietary habits, and training heart rates were represcribed after monthly fitness tests. Forty-two men finished the study. After 24 wk, Vo(2 max) increased by 0.38 +/- 0.14 l/min in the moderate-intensity group and by 0.55 +/- 0.27 l/min in the high-intensity group. Repeated-measures analysis of variance identified a significant interaction between monthly Vo(2 max) score and exercise group (F = 3.37, P < 0.05), indicating that Vo(2 max) responded differently to moderate- and high-intensity exercise. Trend analysis showed that total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and fibrinogen concentrations changed favorably across control, moderate-intensity, and high-intensity groups. However, significant changes in total cholesterol (-0.55 +/- 0.81 mmol/l), low-density lipoprotein cholesterol (-0.52 +/- 0.80 mmol/l), and non-high-density lipoprotein cholesterol (-0.54 +/- 0.86 mmol/l) were only observed in the high-intensity group (all P < 0.05 vs. controls). These data suggest that high-intensity training is more effective in improving cardiorespiratory fitness than moderate-intensity training of equal energy cost. These data also suggest that changes in coronary heart disease risk factors are influenced by exercise intensity.     

Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation

Hydroxymethyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) protect the myocardium against ischemia-reperfusion injury via a mechanism unrelated to cholesterol lowering. Statins may inhibit isoprenylation and thereby prevent activation of proteins such as RhoA. We hypothesized that statins protect the myocardium against ischemia-reperfusion injury via a mechanism involving inhibition of geranylgeranyl pyrophosphate synthesis and translocation of RhoA to the plasma membrane. Sprague-Dawley rats were given either the HMG-CoA reductase inhibitor rosuvastatin, geranylgeranyl pyrophosphate dissolved in methanol, the combination of rosuvastatin and geranylgeranyl pyrophosphate, rosuvastatin and methanol, or distilled water (control) by intraperitoneal injection for 48 h before ischemia-reperfusion. Animals were anesthetized and either subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion where at infarct size was determined, or the expression of RhoA protein was determined in cytosolic and membrane fractions of nonischemic myocardium. There were no significant differences in hemodynamics between the control group and the other groups before ischemia or during ischemia and reperfusion. The infarct size was 80 +/- 3% of the area at risk in the control group. Rosuvastatin reduced infarct size to 64 +/- 2% (P<0.001 vs. control). Addition of geranylgeranyl pyrophosphate (77 +/- 2%, P<0.01 vs. rosuvastatin) but not methanol (65 +/- 2%, not significant vs. rosuvastatin) abolished the cardioprotective effect of rosuvastatin. Geranylgeranyl pyrophosphate alone did not affect infarct size per se (84 +/- 2%). Rosuvastatin increased the cytosol-to-membrane ratio of RhoA protein in the myocardium (P<0.05 vs. control). These changes were abolished by addition of geranylgeranyl pyrophosphate. We conclude that the cardioprotection and the increase of the RhoA cytosol-to-membrane ratio induced by rosuvastatin in vivo are blocked by geranylgeranyl pyrophosphate. The inhibition of geranylgeranyl pyrophosphate formation and subsequent modulation of cytosol/membrane-bound RhoA are of importance for the protective effect of statins against myocardial ischemia-reperfusion injury.     

Selective right, but not left, coronary endothelial dysfunction precedes development of pulmonary hypertension and right heart hypertrophy in rats

We investigated a causal role for coronary endothelial dysfunction in development of monocrotaline (MCT)-induced pulmonary hypertension and right heart hypertrophy in rats. Significant increases in pulmonary pressure and right ventricular weight did not occur until 3 wk after 60 mg/kg MCT injection (34 +/- 4 vs. 19 +/- 2 mmHg and 37 +/- 2 vs. 25 +/- 1% septum + left ventricular weight in controls, respectively). Isolated right coronary arteries (RCA) showed significant decreases in acetylcholine-induced NO dilation in both 1-wk (33 +/- 3% with 0.3 microM; n = 5) and 3-wk (18 +/- 3%; n = 11) MCT rats compared with control rats (71 +/- 8%, n = 10). Septal coronary arteries (SCA) showed a smaller decrease in acetylcholine dilation (55 +/- 8% and 33 +/- 7%, respectively, vs. 73 +/- 8% in controls). No significant change was found in the left coronary arteries (LCA; 88 +/- 6% and 81 +/- 6%, respectively, vs. 87 +/- 3% in controls). Nitro-L-arginine methyl ester-induced vasoconstriction, an estimate of spontaneous endothelial NO-mediated dilation, was not significantly altered in MCT-treated SCA or LCA but was increased in RCA after 1 wk of MCT (-41 +/- 6%) and decreased after 3 wk (-18 +/- 3% vs. -27 +/- 3% in controls). A marked enhancement to 30 nM U-46619-induced constriction was also noted in RCA of 3-wk (-28 +/- 6% vs. -9 +/- 2% in controls) but not 1-wk (-12 +/- 7%) MCT rats. Sodium nitroprusside-induced vasodilation was not different between control and MCT rats. Together, our findings show that a selective impairment of right, but not left, coronary endothelial function is associated with and precedes development of MCT-induced pulmonary hypertension and right heart hypertrophy in rats.